Modulation of Spike-Timing Dependent Plasticity: Towards the Inclusion of a Third Factor in Computational Models

Abstract

In spike-timing dependent plasticity (STDP) change in synaptic strength depends on the timing of pre- vs. postsynaptic spiking activity. Since STDP is in compliance with Hebb’s postulate, it is considered one of the major mechanisms of memory storage and recall. STDP comprises a system of two coincidence detectors with N-methyl-D-aspartate receptor (NMDAR) activation often posited as one of the main components. Numerous studies have unveiled a third component of this coincidence detection system, namely neuromodulation and glia activity shaping STDP. Even though dopaminergic control of STDP has most often been reported, acetylcholine, noradrenaline, nitric oxide (NO), brain-derived neurotrophic factor (BDNF) or gamma-aminobutyric acid (GABA) also has been shown to effectively modulate STDP. Furthermore, it has been demonstrated that astrocytes, via the release or uptake of glutamate, gate STDP expression. At the most fundamental level, the timing properties of STDP are expected to depend on the spatiotemporal dynamics of the underlying signaling pathways. However in most cases, due to technical limitations experiments grant only indirect access to these pathways. Computational models carefully constrained by experiments, allow for a better qualitative understanding of the molecular basis of STDP and its regulation by neuromodulators. Recently, computational models of calcium dynamics and signaling pathway molecules have started to explore STDP emergence in ex and in vivo-like conditions. These models are expected to reproduce better at least part of the complex modulation of STDP as an emergent property of the underlying molecular pathways. Elucidation of the mechanisms underlying STDP modulation and its consequences on network dynamics is of critical importance and will allow better understanding of the major mechanisms of memory storage and recall both in health and disease.

Autonomous emergence of connectivity assemblies via spike triplet interactions

“…The action of different neuromodulators provide a way of modulating the STDP or synaptic transmission 427 functions, and studying the effects of diverse neuromodulatory states on the plasticity of connections in many 428 brain regions is possible with recent advances in experimental techniques [84][85][86]. For instance, timing prop-429 erties of STDP have been shown to depend on the dynamics of the latent signaling pathways involving these 430 factors.…”

“…ity [81], or the location of synaptic inputs on the dendritic tree [82]. However, recent experimental studies 225 have highlighted an important role of neuromodulators in regulating plasticity across the brain [83][84][85][86], as 226 they convey information about novelty or reward. Indeed, neuromodulators such as dopamine, acetylcholine 227 and noradrenaline, but also brain-derived neurotrophic factor (BDNF) and gamma-aminobutyric acid (GABA),…”

A unifying framework for synaptic organization on cortical dendrites

“…Thus, failure to correctly position synapses in development has severe and mostly irreversible consequences during later life (57) and could play a role in neuropsychiatric disorders (11) . However, the minimal model derived from the neurotrophin model is sufficiently general to also be implemented in the adult, where the functional roles of MMP9 and calcium could equivalently be filled by postsynaptic depolarization, NMDA receptor activation, endocannabinoid or nitric oxide signaling or by more complex diffusible plasticity-related products (58) . Thus, our predictions regarding the organization of synapses are not contingent on a specific biophysical implementation of our minimal model as long as it has the three ingredients: distance-and correlationdependent competition and structural plasticity.…”

BDNF controls bidirectional endocannabinoid-plasticity at corticostriatal synapses

“…Synaptic plasticity is tightly controlled by various neuromodulators, also called the third factor (Foncelle et al, 2018), among which, BDNF appears to be indispensable for striatal functions (Baydyuk et al, 2011;Besusso et al, 2013;Unterwald et al, 2013). Indeed, in addition to its prominent role in inducing neuronal proliferation and differentiation, migration and survival, BDNF is a key regulator of synaptic transmission and plasticity in the adult brain (Carvalho et al, 2008;Waterhouse and Xu, 2009;Edelmann et al, 2014;Park et al, 2014).…”

“…Upon various activity-dependent patterns (rate-or spike-timing-coded), corticostriatal synapses exhibit bidirectional plasticity, LTP and LTD, mediated by NMDA and type-1 cannabinoid receptors (CB1Rs), respectively (Di Filippo et al, 2009;Lovinger, 2010). Thus, identifying factors modulating the expression of activity-dependent plasticity (Foncelle et al, 2018) in the striatum is of crucial importance.…”